Background There are few third-line or later (3L+) treatment options for advanced/metastatic (adv/met) gastric cancer/gastroesophageal junction cancers (GC/GEJC). 3L+ Nivolumab demonstrated encouraging results in Asian patients in the ATTRACTION-2 study compared with placebo (12-month survival, 26% vs 11%), and in Western patients in the single-arm CheckMate 032 study (12-month survival, 44%). This analysis aimed to establish comparator cohorts of US patients receiving routine care in real-world (RW) clinical practice. Methods A 2-step matching process generated RW cohorts from Flatiron Health’s oncology database (January 1, 2011–April 30, 2017), for comparison with each trial: (1) clinical trial eligibility criteria were applied; (2) patients were frequency-matched with trial arms for baseline variables significantly associated with survival. Median overall survival (OS) was calculated by Kaplan–Meier analysis from last treatment until death. Results Of 742 adv/met GC/GEJC patients with at least 2 prior lines of therapy, matching generated 90 US RW ATTRACTION-2-matched patients (median OS: 3.5 months) versus 163 ATTRACTION-2 placebo patients (median OS: 4.1 months), and 100 US RW CheckMate 032-matched patients (median OS: 2.9 months) versus 42 CheckMate 032 nivolumab-treated patients (median OS: 8.5 months). Baseline characteristics were generally similar between clinical trial arms and RW-matched cohorts. Conclusions We successfully developed RW cohorts for comparison with data from clinical trials, with comparable baseline characteristics. Survival in US patients receiving RW care was similar to that seen in Asian patients receiving placebo in ATTRACTION-2; survival with nivolumab in CheckMate 032 appeared favorable compared with US RW clinical practice.

Aim: To assess the cost-effectiveness of nivolumab monotherapy for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the US. Methods: We constructed a cohort-based partitioned survival model for three health states (progression-free, progressed disease, and death). Using overall survival and progression-free survival data from the nivolumab and investigator's choice (IC) arms of the CheckMate 141 study, the proportion of patients in each health state was estimated by parametric modeling over a 25-year period. Cost, utility, adverse event, and disease management data inputs were obtained from relevant literature and applied to patients in each health state. A scenario analysis was conducted assuming increased uptake of subsequent immunotherapies. A one-way deterministic sensitivity analysis assessed the impact of variation in multiple parameters. A probabilistic sensitivity analysis in which probabilistic distributions were applied to each input during 1,000 model iterations was also conducted.

No abstract

Introduction: Currently available second-line (2L) therapies for advanced/metastatic esophageal squamous cell carcinoma (adv/met ESCC) include the taxanes paclitaxel and docetaxel. In clinical trials, such therapies have provided only modest improvements in survival. Few studies have assessed outcomes in routine clinical practice in the USA. We compared realworld clinical outcomes in the US for patients receiving taxane or non-taxane 2L therapy for adv/met ESCC. Methods: The Flatiron Health database was used to identify patients diagnosed with adv/ met ESCC (1 January 2011-31 January 2019) who received 2L therapy; index date was date of adv/met diagnosis. Baseline variables and treatment regimens received were identified. Overall survival (OS; 2L start until death or last recorded medical activity) and duration of therapy (DoT; start of 2L therapy until last administration date of 2L therapy) in patients receiving taxane vs. non-taxane-based therapies in the 2L setting were estimated by Kaplan-Meier method. Results: There were no clear differences in baseline characteristics between patients who received 2L taxane therapy (n = 37) and 2L nontaxane therapy (n = 49). Median (95% CI) 2L OS was significantly longer with 2L taxanes (7.3 [5.9-11.5] months) vs. 2L non-taxanes (5.1 [2.9-7.6] months); median (95% CI) 2L DoT was 2.1 (1.8-3.0) months vs. 3.3 (2.6-6.7) months, respectively. Conclusion: Survival was generally poor in patients receiving 2L therapy for adv/met ESCC and was longer in patients receiving 2L taxanes than 2L non-taxane therapy. Efficacious, tolerable therapies for ESCC in the 2L setting are urgently needed.

We explored treatment patterns and outcomes in 3291 real-world patients with advanced/metastatic gastric cancer and gastroesophageal junction cancer. Of these, 75% received first-line therapy, 32% received secondline therapy, 14% received third-line therapy, and 6% received at least 4 lines of therapy (median overall survival: 10.7, 7.6, 6.1, and 2.8 months, respectively). One-quarter of patients received no active treatment after diagnosis. Background: First-line (1L) and second-line (2L) therapies for advanced/metastatic gastric cancer (GC) and gastroesophageal junction cancer (GEJC) have modest efficacy, and therapeutic options in subsequent lines are limited as disease progresses. We assessed real-world treatment patterns and outcomes for advanced/metastatic GC/GEJC. Patients and Methods: Adult patients diagnosed with advanced/metastatic GC/GEJC between January 1, 2011 and April 30, 2018 were identified using the Flatiron Health database. Median overall survival (OS) from start of each line of therapy until death was estimated by the Kaplan-Meier method. Duration of therapy (DoT) was time from start date until end date of each line. Results: We identified 3291 patients with advanced/metastatic GC/GEJC adenocarcinoma. At diagnosis, the median age was 68 years, 60% were white, 53% had initial stage IV disease, and 57% had GC. Of these 3291 patients, most (75%) received at least 1 therapy; 32% received 2L, 14% received third-line (3L) therapy, and 6% received at least 4 lines of therapy (4Lþ). The median OS from start of 1L was 10.7 months (2L, 7.6 months; 3L, 6.1 months; 4Lþ, 2.8 months). The median DoT in 1L was 2.2 months (2L, 2.1 months; 3L, 1.7 months; 4Lþ, 3.0 months). Use of targeted and immunotherapies generally increased progressively with each subsequent line of therapy. Conclusion: One-quarter of patients with advanced/metastatic GC/GEJC remained untreated, and only approximately one-half of patients receiving 1L therapy received subsequent treatment. In all lines of therapy, OS was generally poor and DoT was short. More effective treatment options are needed across all lines of therapy for this highly burdensome disease.

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley& Sons, Ltd.

OBJECTIVES: A multi-dimensional approach to evidence synthesis has previously been explored as an alternative to analysis of hazard ratios (HR) frequently used for time-to-event data. The objective of this study was to explore and compare results using a more complex approach to network meta-analysis (NMA) with those using conventional methods. The methods were applied to an evidence base previously identified to evaluate comparative efficacy for the treatment of advanced breast cancer in postmenopausal women following failure of prior endocrine therapy. METHODS: Data were identified from a published systematic literature review previously conducted in this population; these data were synthesised within a Bayesian NMA utilising fractional polynomial models to estimate relative efficacy between different interventions for overall survival. KaplaneMeier curves reported by all studies were digitised to recreate virtual individual patient data. Extrapolated long-term survival profiles, expected (mean) survival and ranking probabilities were also estimated for each intervention. RESULTS: Seven trials were identified, which assesed seven comparators of interest. Fulvestrant 500 mg was found to be the most effective intervention; mean survival was over 3 years and there was around a 40% chance of fulvestrant 500 mg being ranked as the best treatment over a 10-year time horizon. Findings and trends were consistent with previously published NMAs utilising conventional methodology, synthesising HRs. CONCLUSIONS: A comprehensive approach to evidence synthesis may yield more informative, robust and reliable estimates of comparative efficacy than traditional NMA methods analysing trial-level HRs. These efficacy estimates may subsequently be incorporated into cost-effectiveness models without the assumption of proportional hazards between treatment arms that underpins the use of HRs, which have been shown to be a limited measure of treatment effect. An alternative approach to synthesis, utilising fractional polynomials models, may lead to more informed decision-making, which is critical when there are budget constraints associated with reimbursement of new interventions.

1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats.